Diabetes and Atherosclerosis
Diabetes and Atherosclerosis
More Than a "Lifeless Tube"
Peter Libby, MD, Harvard Medical School, Boston, Massachusetts, discussed the biology of the atheromatous plaque, contrasting the traditional view of the artery wall as a "lifeless tube" in which atherosclerotic material is "caking up like rust" with our new understanding that the vessel wall has a complex cellular metabolism characterized by inflammatory and ultimately thrombotic processes that lead to atherosclerosis. Understanding the molecular biology of the artery will lead to advances in clinical treatment.
The entry of inflammatory cells into the mechanically or metabolically injured artery is initiated by leukocyte adhesion molecules expressed on the endothelium, leading to the capture of specific circulating leukocytes. Vascular cell adhesion molecule-1 (VCAM-1) binds monocytes and lymphocytes, the cell types found in atheromata. VCAM-1 is inducible by cytokines, appears in the presence of metabolic injury such as hyperglycemia and dyslipidemia, and plays a role in the development of both early and more advanced lesions. Monocyte penetration, required for the initiation of atherogenesis, is amplified by chemokines such as monocyte chemoattractant protein-1 (MCP-1), a potent product of endothelial and smooth muscle cells that is localized in human and experimental atheroma. The use of genetic mouse models has led to evidence that MCP-1 plays a causal role; MCP-1-deficient mice do not express the LDL-receptor and show reduced lipid deposition and lesion formation.
Chemokines are cytokines that control the positioning of cells in tissues and the recruitment of leukocytes to the site of inflammation. CXC chemokines, which have paired cysteines separated by a different amino acid, include interleukin (IL)-8, which interacts with the CXC receptor-2 (CXCR-2), and interferon (IFN) gamma-inducible protein-10, which interacts with CXCR-3. Dr. Libby noted that new research suggests a role for mast cells in atherosclerosis. The chemokine stromal cell-derived factor-1 (SDF-1) also activates platelets, suggesting a link with thrombosis. After monocytes enter the arterial wall, they become tissue macrophages, changing characteristics and ultimately becoming foam cells, which are a major component of lesion progression. Macrophage colony-stimulating factor (M-CSF) is present in atherosclerotic lesions, with the op mutation resulting in defective M-CSF and causing reduced atheroma formation in the LDL receptor-deficient mouse. Thus, Dr. Libby suggested, the cytokines VCAM-1, MCP-1, and M-CSF are crucial to the early processes of atherogenesis.
Plumber's View of Atherosclerosis as a "Rusty Pipe"
The later phases of the disease are manifest clinically as "a growing epidemic" after behaving in a clinically silent fashion for many years. Dr. Libby further questioned the traditional "plumber's view" of atherosclerosis as a "rusty pipe" on the basis of new clinical data. In a study of 60 persons during first myocardial infarction after thrombolysis, residual stenosis was < 60% in 28 persons, so that the severity of coronary artery stenosis of the "culprit lesion" is below the level currently considered to require intervention in approximately two thirds of cases. "Those are the substrates of most myocardial infarctions.... Atherosclerosis is a disease not of the lumen but of the artery wall," Dr. Libby said. Only in the late stages is there evidence of stenosis. Intravascular ultrasound (IVUS) shows that eccentrically remodeled atheromata are not visible angiographically. Disparity between lumen narrowing and actual extent of plaque "is the rule." Plaque rupture followed by thrombosis is the usual course of clinical events. The fibrous cap of the plaque is made up of collagen fibrils with great tensile strength, but with tightly regulated synthesis and degradation. The matrix metalloproteinase (MMP) family initiates cleavage of the collagen molecule, allowing subsequent collagenolysis by other enzymes. Cleaved collagen is colocalized with MMP-1 and MMP-13 in human atheromata. The control of MMPs is orchestrated by leukocytes. IFN gamma can decrease collagen synthesis. After the plaque weakens and ruptures, tissue factor (TF), a procoagulant produced by a subpopulation of macrophages, is expressed in the atherosclerotic plaque. CD 40 ligand mediates TF formation in atheroma. Thus, inflammation regulates both the stability of fibrous plaque and the thrombogenicity of the lipid core. These considerations lead to the concept of a "vulnerable plaque." One must realize, Dr. Libby pointed out, that there is no single lesion; rather, there are multiple lesions in the patient at risk. Recurrent events are more common in persons with multiple complex plaques.
In fact, the inflammation present in persons with atherosclerosis is actually systemic. Myeloperoxidase, an enzyme released by activated granulocytes and a monocyte subpopulation, is bound to the extracellular matrix at sites of inflammation and converts complement factor I (CI) present in sites of thrombosis. Cardiac venous sampling shows a "step up" of inflammatory mediators across the cardiac circulation in persons with unstable coronary syndromes. Revascularization strategies, then, although ideal for angina, may not prolong life or prevent myocardial infarction, because local intervention directed at the "tight stenosis" does not stabilize plaque, which requires metabolic intervention. Thus, after revascularization, it is necessary to "modify the underlying biology" both with lifestyle modification and drug therapy. Statins appear to decrease coronary events in a dose-related fashion, as reported in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study of pravastatin 40 mg daily vs atorvastatin 80 mg daily. In this study, LDL cholesterol level of 95 vs 70 was associated with 26.3% vs 22.4% risk of recurrent events at 30 months. There is growing evidence that fibrates and thiazolidinediones may play a role in reducing atherosclerosis as well.
The Role of Magnetic Resonance Imaging (MRI)
Valentin Fuster, MD, PhD, Mount Sinai Medical Center, New York, NY, discussed the role of MRI in understanding and managing the interrelationship between diabetes and atherosclerosis. He focused on neovascularization and inflammation of the vessel wall not only as mediators but also as potential ways of learning how to induce regression of atherosclerosis. Diabetes dramatically increases the risk of cardiovascular disease. Obesity, whether genetic or environmental in etiology, accelerates the production of macrophages and visceral adipocytes, leading to insulin resistance, dyslipidemia, hypertension, and cytokine release -- all contributing to worsening atherosclerosis. Therefore, in a sense, Dr. Fuster said, "diabetes is no more than a marker."
New vessel formation accelerates atherosclerosis. LDL entry into the arterial wall activates monocyte entry and growth of the vasa vasorum, which may be looked at as defense mechanisms to remove oxidized LDL particles. The entry of new vessels, however, leads to rupture of the internal elastic lamina, which potentiates the process of outward expansion of atherosclerotic lesions. MRI, Dr. Fuster said, "gives us an understanding of the atherosclerotic process." The development of the atherosclerotic process is eccentric until the end stages of luminal narrowing. In the hypercholesterolemic rabbit model and in human studies of the abdominal aorta (which has the highest rate of plaque rupture of any vessel, but which, because of rapid blood flow, is associated with low likelihood of thrombus), autopsy studies show new vasa vasorum in outer portions of the vessel. The arterial media of persons with diabetes contain large numbers of erythrocytes, suggesting leakage of vasa vasorum, which may lead to macrophage entry with subsequent weakening of the internal elastic lamina. This association of erythrocyte leakage with diabetes suggests a microangiopathic process, with "diabetic microvessels having something that makes them much more dangerous." The autopsy studies showed the number of vasa vasorum to be the strongest predictor of plaque disruption. Dr. Fuster showed videos of high-resolution ultrasound studies with microbubbles which demonstrate that in humans with atherosclerosis, vasa vasorum are present in the carotid near areas of lipid deposition. Thus, a new paradigm of atherosclerosis suggests that lipid deposition increases the development of vasa vasorum, which cause inflammatory changes, ultimately leading to rupture of internal elastic lamina.
This new concept explains certain aspects of the effect of cholesterol lowering. Studies in a porcine model show dramatic decreases in the vasa vasorum with simvastatin. In a study comparing simvastatin at doses of 20 mg vs 80 mg daily in persons with aortic and carotid plaques, lipid layers decrease without change in the fibrous layer of the plaque, suggesting exit via other mechanisms. LDL cholesterol level < 100 was associated with greater degrees of regression, rather than there being an effect of the dose per se. A recent meta-regression analysis of persons with and without diabetes that addressed the effect of lipid lowering suggests that in people with diabetes, much greater LDL cholesterol lowering is required for a given degree of protection against cardiovascular events, a phenomenon also seen with blood pressure-lowering requirements. On the basis of these considerations, Dr. Fuster suggested that an LDL cholesterol level of 100 mg/dL in a person with diabetes may be excessively high, so that even greater degrees of cholesterol lowering may be appropriate. He mentioned that aspirin not only prevents platelet aggregation, but also has anti-inflammatory effects, with "evolving evidence that the dose of aspirin has to be larger [than 81 mg]."
Dr. Fuster noted that the monocyte may be seen as a defense mechanism against oxidized LDL present in the arterial wall, but one that can "lead to a blood clot if you leave it until too late." Inflammatory processes occur not just in the plaque but also in the blood of persons with atherosclerosis, and it is therefore important to study circulating factors increasing thrombosis. TF has been characterized over the past decade on the basis of studies suggesting that it is an important monocyte secretory product. An important question is why the monocyte, which from a teleological view should be seen as a defense mechanism, should lead to adverse outcomes. Studies with monocytes containing excess oxidized LDL show that the cell undergoes apoptosis, leading to the release of toxic factors, suggesting that products such as TF are only seen when "the cell is struggling." Importantly, studies of ruptured plaques in diabetes show more monocytes, more thrombus, and more TF, further suggesting the atherogenic effect of hyperglycemia. Using a perfusion chamber to measure the propensity of blood to clot, factors that were found to be particularly thrombogenic were diabetes, hyperlipidemia, and cigarette smoking. Dr. Fuster showed evidence that fragments of apoptotic monocytes circulate in the blood in such patients, leading to the particularly hypercoagulable state. Blood thrombogenicity may be decreased by aggressive diabetes treatment, particularly with thiazolidinediones. Interestingly, the "active clot" following myocardial infarction or seen in unstable angina is highly thrombogenic, perhaps explaining the increased risk during the 4- to 6-week period following an initial event.
Activated macrophages capture oxidized LDL, preparing it for uptake by HDL particles, a process that cannot occur when the cells are exposed to an excess of fat. Conceptually, a way to address this adverse effect of excessive LDL cholesterol would be to raise the HDL level. Administration of human HDL in a rabbit model leads to regression of aortic fatty streaks. This effect can be demonstrated in humans, with studies of administration of aopA-I Milano showing reversal of atherosclerosis. "The best antithrombotic," Dr. Fuster commented, "is HDL," which reverses the prothrombotic process leading to atherosclerosis. Some effects of thiazolidinedione treatment may involve similar phenomena.
Studies are being conducted comparing the antiatherosclerotic effects of treatment with statins alone or in combination with thiazolidinediones or fibrates in persons with diabetes. The coronary calcium score is being measured by computerized tomography (CT); magnetic resonance angiography is being performed to assess areas of arterial narrowing; contrast-enhanced CT is being performed to visualize the coronary circulation using "fly through" computerized 3-dimensional reconstruction technology; targeted MRI is being used to visualize and characterize plaque as fibrotic vs lipid-laden. These new technologies can add to our existing understanding based on traditional risk factors. For example, data suggest that combining the Framingham risk score with the coronary calcium assessment score improves cardiovascular disease risk assessment. Limitations of CT are that it cannot characterize plaque in the fashion possible with MRI and that a moderately high dose of radiation is required. The use of all these technologies will allow greater understanding of potential approaches to reduce atherosclerosis, often with relatively small numbers of treated patients. A pilot study is being conducted, for example, assessing the effect of nicotinic acid treatment using MRI.
Dr. Fuster ended his discussion by mentioning the use of "coated stents," which appear to decrease the likelihood of restenosis following angioplasty. He has been involved in the development of the Freedom Trial, a prospective multicenter clinical trial of patients with diabetes and multivessel coronary disease randomized either to percutaneous coronary intervention with sirolimus or paclitaxel drug-eluting stents or coronary artery bypass grafting to test which treatment is superior in preventing mortality, nonfatal myocardial infarction, and stroke.
References
Peter Libby, MD, Harvard Medical School, Boston, Massachusetts, discussed the biology of the atheromatous plaque, contrasting the traditional view of the artery wall as a "lifeless tube" in which atherosclerotic material is "caking up like rust" with our new understanding that the vessel wall has a complex cellular metabolism characterized by inflammatory and ultimately thrombotic processes that lead to atherosclerosis. Understanding the molecular biology of the artery will lead to advances in clinical treatment.
The entry of inflammatory cells into the mechanically or metabolically injured artery is initiated by leukocyte adhesion molecules expressed on the endothelium, leading to the capture of specific circulating leukocytes. Vascular cell adhesion molecule-1 (VCAM-1) binds monocytes and lymphocytes, the cell types found in atheromata. VCAM-1 is inducible by cytokines, appears in the presence of metabolic injury such as hyperglycemia and dyslipidemia, and plays a role in the development of both early and more advanced lesions. Monocyte penetration, required for the initiation of atherogenesis, is amplified by chemokines such as monocyte chemoattractant protein-1 (MCP-1), a potent product of endothelial and smooth muscle cells that is localized in human and experimental atheroma. The use of genetic mouse models has led to evidence that MCP-1 plays a causal role; MCP-1-deficient mice do not express the LDL-receptor and show reduced lipid deposition and lesion formation.
Chemokines are cytokines that control the positioning of cells in tissues and the recruitment of leukocytes to the site of inflammation. CXC chemokines, which have paired cysteines separated by a different amino acid, include interleukin (IL)-8, which interacts with the CXC receptor-2 (CXCR-2), and interferon (IFN) gamma-inducible protein-10, which interacts with CXCR-3. Dr. Libby noted that new research suggests a role for mast cells in atherosclerosis. The chemokine stromal cell-derived factor-1 (SDF-1) also activates platelets, suggesting a link with thrombosis. After monocytes enter the arterial wall, they become tissue macrophages, changing characteristics and ultimately becoming foam cells, which are a major component of lesion progression. Macrophage colony-stimulating factor (M-CSF) is present in atherosclerotic lesions, with the op mutation resulting in defective M-CSF and causing reduced atheroma formation in the LDL receptor-deficient mouse. Thus, Dr. Libby suggested, the cytokines VCAM-1, MCP-1, and M-CSF are crucial to the early processes of atherogenesis.
Plumber's View of Atherosclerosis as a "Rusty Pipe"
The later phases of the disease are manifest clinically as "a growing epidemic" after behaving in a clinically silent fashion for many years. Dr. Libby further questioned the traditional "plumber's view" of atherosclerosis as a "rusty pipe" on the basis of new clinical data. In a study of 60 persons during first myocardial infarction after thrombolysis, residual stenosis was < 60% in 28 persons, so that the severity of coronary artery stenosis of the "culprit lesion" is below the level currently considered to require intervention in approximately two thirds of cases. "Those are the substrates of most myocardial infarctions.... Atherosclerosis is a disease not of the lumen but of the artery wall," Dr. Libby said. Only in the late stages is there evidence of stenosis. Intravascular ultrasound (IVUS) shows that eccentrically remodeled atheromata are not visible angiographically. Disparity between lumen narrowing and actual extent of plaque "is the rule." Plaque rupture followed by thrombosis is the usual course of clinical events. The fibrous cap of the plaque is made up of collagen fibrils with great tensile strength, but with tightly regulated synthesis and degradation. The matrix metalloproteinase (MMP) family initiates cleavage of the collagen molecule, allowing subsequent collagenolysis by other enzymes. Cleaved collagen is colocalized with MMP-1 and MMP-13 in human atheromata. The control of MMPs is orchestrated by leukocytes. IFN gamma can decrease collagen synthesis. After the plaque weakens and ruptures, tissue factor (TF), a procoagulant produced by a subpopulation of macrophages, is expressed in the atherosclerotic plaque. CD 40 ligand mediates TF formation in atheroma. Thus, inflammation regulates both the stability of fibrous plaque and the thrombogenicity of the lipid core. These considerations lead to the concept of a "vulnerable plaque." One must realize, Dr. Libby pointed out, that there is no single lesion; rather, there are multiple lesions in the patient at risk. Recurrent events are more common in persons with multiple complex plaques.
In fact, the inflammation present in persons with atherosclerosis is actually systemic. Myeloperoxidase, an enzyme released by activated granulocytes and a monocyte subpopulation, is bound to the extracellular matrix at sites of inflammation and converts complement factor I (CI) present in sites of thrombosis. Cardiac venous sampling shows a "step up" of inflammatory mediators across the cardiac circulation in persons with unstable coronary syndromes. Revascularization strategies, then, although ideal for angina, may not prolong life or prevent myocardial infarction, because local intervention directed at the "tight stenosis" does not stabilize plaque, which requires metabolic intervention. Thus, after revascularization, it is necessary to "modify the underlying biology" both with lifestyle modification and drug therapy. Statins appear to decrease coronary events in a dose-related fashion, as reported in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study of pravastatin 40 mg daily vs atorvastatin 80 mg daily. In this study, LDL cholesterol level of 95 vs 70 was associated with 26.3% vs 22.4% risk of recurrent events at 30 months. There is growing evidence that fibrates and thiazolidinediones may play a role in reducing atherosclerosis as well.
The Role of Magnetic Resonance Imaging (MRI)
Valentin Fuster, MD, PhD, Mount Sinai Medical Center, New York, NY, discussed the role of MRI in understanding and managing the interrelationship between diabetes and atherosclerosis. He focused on neovascularization and inflammation of the vessel wall not only as mediators but also as potential ways of learning how to induce regression of atherosclerosis. Diabetes dramatically increases the risk of cardiovascular disease. Obesity, whether genetic or environmental in etiology, accelerates the production of macrophages and visceral adipocytes, leading to insulin resistance, dyslipidemia, hypertension, and cytokine release -- all contributing to worsening atherosclerosis. Therefore, in a sense, Dr. Fuster said, "diabetes is no more than a marker."
New vessel formation accelerates atherosclerosis. LDL entry into the arterial wall activates monocyte entry and growth of the vasa vasorum, which may be looked at as defense mechanisms to remove oxidized LDL particles. The entry of new vessels, however, leads to rupture of the internal elastic lamina, which potentiates the process of outward expansion of atherosclerotic lesions. MRI, Dr. Fuster said, "gives us an understanding of the atherosclerotic process." The development of the atherosclerotic process is eccentric until the end stages of luminal narrowing. In the hypercholesterolemic rabbit model and in human studies of the abdominal aorta (which has the highest rate of plaque rupture of any vessel, but which, because of rapid blood flow, is associated with low likelihood of thrombus), autopsy studies show new vasa vasorum in outer portions of the vessel. The arterial media of persons with diabetes contain large numbers of erythrocytes, suggesting leakage of vasa vasorum, which may lead to macrophage entry with subsequent weakening of the internal elastic lamina. This association of erythrocyte leakage with diabetes suggests a microangiopathic process, with "diabetic microvessels having something that makes them much more dangerous." The autopsy studies showed the number of vasa vasorum to be the strongest predictor of plaque disruption. Dr. Fuster showed videos of high-resolution ultrasound studies with microbubbles which demonstrate that in humans with atherosclerosis, vasa vasorum are present in the carotid near areas of lipid deposition. Thus, a new paradigm of atherosclerosis suggests that lipid deposition increases the development of vasa vasorum, which cause inflammatory changes, ultimately leading to rupture of internal elastic lamina.
This new concept explains certain aspects of the effect of cholesterol lowering. Studies in a porcine model show dramatic decreases in the vasa vasorum with simvastatin. In a study comparing simvastatin at doses of 20 mg vs 80 mg daily in persons with aortic and carotid plaques, lipid layers decrease without change in the fibrous layer of the plaque, suggesting exit via other mechanisms. LDL cholesterol level < 100 was associated with greater degrees of regression, rather than there being an effect of the dose per se. A recent meta-regression analysis of persons with and without diabetes that addressed the effect of lipid lowering suggests that in people with diabetes, much greater LDL cholesterol lowering is required for a given degree of protection against cardiovascular events, a phenomenon also seen with blood pressure-lowering requirements. On the basis of these considerations, Dr. Fuster suggested that an LDL cholesterol level of 100 mg/dL in a person with diabetes may be excessively high, so that even greater degrees of cholesterol lowering may be appropriate. He mentioned that aspirin not only prevents platelet aggregation, but also has anti-inflammatory effects, with "evolving evidence that the dose of aspirin has to be larger [than 81 mg]."
Dr. Fuster noted that the monocyte may be seen as a defense mechanism against oxidized LDL present in the arterial wall, but one that can "lead to a blood clot if you leave it until too late." Inflammatory processes occur not just in the plaque but also in the blood of persons with atherosclerosis, and it is therefore important to study circulating factors increasing thrombosis. TF has been characterized over the past decade on the basis of studies suggesting that it is an important monocyte secretory product. An important question is why the monocyte, which from a teleological view should be seen as a defense mechanism, should lead to adverse outcomes. Studies with monocytes containing excess oxidized LDL show that the cell undergoes apoptosis, leading to the release of toxic factors, suggesting that products such as TF are only seen when "the cell is struggling." Importantly, studies of ruptured plaques in diabetes show more monocytes, more thrombus, and more TF, further suggesting the atherogenic effect of hyperglycemia. Using a perfusion chamber to measure the propensity of blood to clot, factors that were found to be particularly thrombogenic were diabetes, hyperlipidemia, and cigarette smoking. Dr. Fuster showed evidence that fragments of apoptotic monocytes circulate in the blood in such patients, leading to the particularly hypercoagulable state. Blood thrombogenicity may be decreased by aggressive diabetes treatment, particularly with thiazolidinediones. Interestingly, the "active clot" following myocardial infarction or seen in unstable angina is highly thrombogenic, perhaps explaining the increased risk during the 4- to 6-week period following an initial event.
Activated macrophages capture oxidized LDL, preparing it for uptake by HDL particles, a process that cannot occur when the cells are exposed to an excess of fat. Conceptually, a way to address this adverse effect of excessive LDL cholesterol would be to raise the HDL level. Administration of human HDL in a rabbit model leads to regression of aortic fatty streaks. This effect can be demonstrated in humans, with studies of administration of aopA-I Milano showing reversal of atherosclerosis. "The best antithrombotic," Dr. Fuster commented, "is HDL," which reverses the prothrombotic process leading to atherosclerosis. Some effects of thiazolidinedione treatment may involve similar phenomena.
Studies are being conducted comparing the antiatherosclerotic effects of treatment with statins alone or in combination with thiazolidinediones or fibrates in persons with diabetes. The coronary calcium score is being measured by computerized tomography (CT); magnetic resonance angiography is being performed to assess areas of arterial narrowing; contrast-enhanced CT is being performed to visualize the coronary circulation using "fly through" computerized 3-dimensional reconstruction technology; targeted MRI is being used to visualize and characterize plaque as fibrotic vs lipid-laden. These new technologies can add to our existing understanding based on traditional risk factors. For example, data suggest that combining the Framingham risk score with the coronary calcium assessment score improves cardiovascular disease risk assessment. Limitations of CT are that it cannot characterize plaque in the fashion possible with MRI and that a moderately high dose of radiation is required. The use of all these technologies will allow greater understanding of potential approaches to reduce atherosclerosis, often with relatively small numbers of treated patients. A pilot study is being conducted, for example, assessing the effect of nicotinic acid treatment using MRI.
Dr. Fuster ended his discussion by mentioning the use of "coated stents," which appear to decrease the likelihood of restenosis following angioplasty. He has been involved in the development of the Freedom Trial, a prospective multicenter clinical trial of patients with diabetes and multivessel coronary disease randomized either to percutaneous coronary intervention with sirolimus or paclitaxel drug-eluting stents or coronary artery bypass grafting to test which treatment is superior in preventing mortality, nonfatal myocardial infarction, and stroke.
References
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Li H, Cybulsky MI, Gimbrone MA Jr, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993;13:197-204.
Gu L, Okada Y, Clinton SK, et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998;2:275-281.
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Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J. 1988;9:1317-1323.
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Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation. 1997;96:396-399.
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Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27:813-823.
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Fayad ZA, Fuster V, Fallon JT, et al. Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging. Circulation. 2000;102:506-510.
Helft G, Worthley SG, Fuster V, et al. Progression and regression of atherosclerotic lesions: monitoring with serial noninvasive magnetic resonance imaging. Circulation. 2002;105:993-998.
Wilson SH, Herrmann J, Lerman LO, et al. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering. Circulation. 2002;105:415-418.
Corti R, Fuster V, Fayad ZA, et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation. 2002;106:2884-2887.
Fisher M. Diabetes and atherogenesis. Heart. 2004;90:336-340.
Banner DW, D'Arcy A, Chene C, et al. The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor. Nature. 1996;380:41-46.
Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94:3090-3097.
Moreno PR, Murcia AM, Palacios IF, et al. Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Circulation. 2000;102:2180-2184.
Osende JI, Badimon JJ, Fuster V, et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol. 2001;38:1307-1312.
Sambola A, Osende J, Hathcock J, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation. 2003;107:973-977.
Li AC, Glass CK. The macrophage foam cell as a target for therapeutic intervention. Nat Med. 2002;8:1235-1242.
Badimon JJ, Badimon L, Galvez A, Dische R, Fuster V. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest. 1989;60:455-461.
Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest. 1990;85:1234-1241.
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292-2300.
Corti R, Osende JI, Fallon JT, et al. The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging. J Am Coll Cardiol. 2004;43:464-473.
Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291:210-215.
Poon M, Badimon JJ, Fuster V. Overcoming restenosis with sirolimus: from alphabet soup to clinical reality. Lancet. 2002;359:619-622.